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Table of Contents
Year : 2022  |  Volume : 12  |  Issue : 2  |  Page : 61-69

Intensive care unit delirium in patients with severe COVID-19: A prospective observational cohort study

1 Department of Internal Medicine, Mayo Clinic School of Graduate Medical Education, Mayo Clinic, Rochester, Minnesota, USA
2 Division of Psychiatry, Mayo Clinic Florida; Department of Neurology, Mayo Clinic Florida, Florida, USA
3 Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Phoenix, Arizona, USA
4 Department of Critical Care Medicine, Mayo Clinic Arizona; Division of Pulmonary Medicine, Mayo Clinic Arizona, Phoenix, Arizona, USA

Date of Submission01-Nov-2021
Date of Acceptance10-Dec-2021
Date of Web Publication24-Jun-2022

Correspondence Address:
Dr. Rodrigo Cartin-Ceba
5777 East Mayo Boulevard, Phoenix, Arizona 85054
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijciis.ijciis_93_21

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Background: Delirium is common in patients with severe coronavirus disease-19 (COVID-19). The purpose of our study was to determine whether severe COVID-19 is an independent risk factor for the development of delirium in patients treated in the intensive care unit (ICU).
Methods: This prospective observational cohort study involved 162 critically ill patients admitted to a multidisciplinary ICU during 2019 and 2020. A validated screening tool was used to diagnose delirium. Multiple delirium risk factors were collected daily including clinical characteristics, hospital course, lab values, vital signs, surgical exposure, drug exposure, and COVID-19 characteristics. After univariate analysis, a multivariate logistic regression analysis was performed to determine independent risk factors associated with the development of delirium.
Results: In our study population, 50 (31%) patients developed delirium. A total of 39 (24.1%) tested positive for COVID-19. Initial analysis showed COVID-19 to be more prevalent in those patients that developed delirium (40% vs. 17%; P = 0.003). Multivariate analysis showed opioid use (odds ratio [OR]: 24 [95% confidence intervals (CI): 16–27]; P ≤ 0.001), benzodiazepine use (OR: 23 [95% CI: 16–63] P = 0.001), and estimated mortality based on acute physiology and chronic health evaluation IV score (OR: 1.04 [95% CI: 1.01–1.07] P = 0.002) to be independently associated with delirium development. COVID-19 (OR: 1.44 [95% CI: 0.13–10.6]; P = 0.7) was not found to be associated with delirium.
Conclusion: Delirium is prevalent in critically ill patients admitted to the ICU, including those with COVID-19. However, after adjustment for important covariates, we found in this cohort that COVID-19 was not an independent risk factor for delirium.

Keywords: Coronavirus disease-19, delirium, encephalopathy, intensive care unit, neuroinflammation, severe acute respiratory syndrome coronavirus 2

How to cite this article:
Smith RJ, Lachner C, Singh VP, Cartin-Ceba R. Intensive care unit delirium in patients with severe COVID-19: A prospective observational cohort study. Int J Crit Illn Inj Sci 2022;12:61-9

How to cite this URL:
Smith RJ, Lachner C, Singh VP, Cartin-Ceba R. Intensive care unit delirium in patients with severe COVID-19: A prospective observational cohort study. Int J Crit Illn Inj Sci [serial online] 2022 [cited 2023 Mar 23];12:61-9. Available from: https://www.ijciis.org/text.asp?2022/12/2/61/348013

   Introduction Top

Coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is notorious because of its impact on the respiratory system.[1],[2],[3],[4] Intensive care is often required in these patients due to the severe respiratory failure that can result from COVID-19;[4] approximately one-quarter of those hospitalized require treatment in the intensive care unit (ICU) due to refractory hypoxemia, shock, or multiple organ failure.[5] However, as we approach the second anniversary of the global pandemic, evidence continues to emerge demonstrating that the effect of this virus reaches far beyond the lungs. Due to the broad tropism of SARS-CoV-2, such effects include gastrointestinal, renal, hepatic, cardiac, and neurologic manifestations.[1],[2],[3],[4],[6],[7],[8],[9],[10],[11],[12],[13],[14]

Delirium, which is associated with disturbances in consciousness, attention, perception, and behavior, is an organic brain syndrome with a fluctuating course.[6],[9],[14],[15] It is an independent predictor of mortality, increased length of stay, ventilator utilization, and lasting cognitive impairment.[1],[2],[4],[6],[7],[9],[10],[11],[12],[13] Delirium has long been considered an indicator of systemic critical illness.[7],[9],[11],[13] In COVID-19, the World Health Organization has recognized delirium as a core symptom of SARS-CoV-2 infection;[1],[6] interestingly, delirium may be the only finding in those without overt respiratory symptoms.[1],[2],[6],[10],[14] Furthermore, a recent meta-analysis found that delirium is associated with and has the potential to predict, which patients will experience higher morbidity and mortality as a result of COVID-19.[15]

Early studies from Wuhan describe neurologic symptoms of SARS-CoV-2 infection; “impaired consciousness” was seen in 7.5% of patients in one of the first retrospective reviews reporting central nervous system (CNS) dysfunction.[7],[8],[16] However, such cases were likely underreported as a validated delirium screening tool was not utilized.[11] Recent studies have suggested that delirium commonly occurs in COVID-19 patients with frequency increasing in relation to the severity of illness.[1],[2],[7],[13],[17],[18],[19],[20],[21],[22] The prevalence of delirium has been reported to range from 65% to 79.5% in those COVID-19 patients admitted to the ICU.[1],[2],[11],[19],[22] However, delirium is prevalent in those requiring intensive care for any reason.[4],[7],[8],[9],[13]

Although it has been postulated that delirium occurs in greater frequency than would otherwise be expected in COVID-19 patients,[7],[12],[17] whether SARS-CoV-2 infection is an independent risk factor for delirium has not been clearly established. Additional factors that contribute to the development of delirium in COVID-19 patients include those associated with pneumonia and ARDS, such as hypoxia and respiratory acidosis.[1],[2],[6],[8],[19],[23] ICU admission, the administration of deliriogenic drugs, and the social isolation that results from quarantine further increase the likelihood of developing delirium in these susceptible patients.[1],[4],[6],[7],[9],[11],[14],[19],[24]

In a prospective cohort of consecutively admitted patients to a multidisciplinary ICU, we aimed to investigate whether SARS-CoV-2 infection is an independent risk factor for developing delirium in those patients suffering from severe COVID-19.

   Methods Top

Study population

This prospective observational cohort study was conducted from May 1, 2019 to October 31, 2020 at a 30-bed multidisciplinary ICU in Mayo Clinic Hospital, Phoenix, Arizona. This ICU is fully staffed by intensivists 24/7. Approval was provided by the Mayo Institutional Review Board (IRB) before initiation of data collection; the need for patient consent was waived. This study was performed in accordance with the Helsinki Declaration pertaining to medical research involving human subjects.

Daily ICU admissions were screened by the investigators for the assessment of inclusion and exclusion criteria. Inclusion criteria: consecutive critically ill patients ≥18 years of age admitted to the ICU during the study period; for COVID-19 patients, a COVID-19 polymerase chain reaction (PCR) test positive within 14 days. Exclusion criteria include patients whose code status is either do no resuscitate or do not intubate (DNR/DNI) and comfort care patients, presence of delirium at the time of ICU admission, and patients who had not agreed to the use of their medical records for research. Furthermore, those patients with a history of substance abuse, psychiatric disease, cognitive impairment, incarcerated persons, and pregnant persons were excluded as vulnerable populations in accordance with the IRB this study was performed under. When patients required readmission to the ICU after discharge, only data from the first admission were analyzed.

Data collection

Comprehensive data on patient characteristics, hospital course, laboratory values, vital signs, surgical procedures, and medication administration were collected on all study enrolled patients during the course of their hospitalization. The validated confusion assessment method for the ICU (CAM-ICU) screening tool was used to diagnose delirium in our study population.[25] The CAM-ICU tool is administered by Mayo Clinic ICU nursing staff every 8 h or when a mental status change is noted. Positive and negative CAM-ICU results are documented in the electronic health record as events occurring during the following 5-h windows: 0:00–4:00; 4:00–8:00; 8:00–12:00; 12:00–16:00; 16:00–20:00; and 20:00–24:00. The prerequisite to inclusion in the delirium group was positive screening test on two consecutive administrations of the CAM-ICU.

For the purpose of our study, we defined delirium in accordance with the American Psychiatric Association's Diagnostic and Statistical of Mental Disorders, 5th edition.[26] That definition states that delirium is a disturbance of attention, cognition, and awareness that develops over a short period of time, represents an acute change from baseline attention and awareness, and tends to fluctuate in severity throughout the course of a day. Such disturbance must not better explained by another preexisting, evolving, or established neurocognitive disorder and does not occur in the context of a severely reduced level of arousal, such as coma. Finally, the definition requires evidence from the patient's history, physical examination, or laboratory results that the disturbance is caused by a medical condition, substance intoxication or withdrawal, or medication side effect. Furthermore, we utilized the Third International Consensus Definitions (Sepsis-3) to define both sepsis and septic shock.[27]

In those patients that underwent surgical procedures, inhaled anesthetic exposure, medication administration, and surgery characteristics data were also collected. Vital signs and laboratories were collected during the first ICU day; worse values were abstracted. The acute physiology score (APS), acute physiology and chronic health evaluation score (APACHE IV), and predicted hospital mortality rates based on these scores were calculated using an online APACHE IV calculator.[28] Daily sequential organ failure assessment score[29] was documented daily from day 1 to day 7. Unobtainable missing data would have resulted in list-wise deletion; however, this strategy was not required in our dataset.


All data are summarized as median (interquartile range) or percentages. Unpaired Student's t-tests will be used to compare continuous variables with normal distribution and the Wilcoxon rank test for skewed distribution. For comparison of categorical variables, Chi-square tests will be used if the number of elements in each cell was ≥5; Fisher's exact test will be used otherwise. For the assessment of independent predictors of delirium, we created a multiple logistic regression model by entering covariates that showed significant differences (P < 0.1) between those that develop or not delirium. The model was refined with backward stepwise regression, considering colinearity and interaction terms. When appropriate, the odds ratio (OR) and 95% confidence intervals (CI) were calculated. Model discrimination was assessed using receiving operator curves. Model fit (calibration) was assessed using the Hosmer-Lemeshow goodness-of-fit test. A P ≤ 0.05 was considered statistically significant. All data analyses were performed using JMP Statistical Software (Version 14.1.0; SAS Institute, Cary, NC, USA).

   Results Top

A total of 162 patients were included in the study; 50 of whom developed delirium during their hospitalization. Description of the study population, data on the hospital course of each group, as well as laboratory values and vital signs are provided in [Table 1], [Table 2], [Table 3], respectively. The study cohort includes 39 (24.1%) COVID-19-positive patients. Univariate analysis suggested that COVID-19 was more commonly observed in the delirium population. Both APS and APACHE IV were higher in the group that developed delirium. Sepsis and septic shock were more commonly associated with the delirium group in the univariate analysis. Furthermore, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), immunosuppression, tachycardia, tachypnea, mechanical ventilation, leukocytosis, and acidemia were also more commonly identified in the population that developed delirium. The delirium group also experienced increased ICU and hospital lengths of stay (LOS).
Table 1: Patient characteristics

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Table 2: Hospital course

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Table 3: Labs and vitals

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Information related to surgical risk factors associated with delirium in our patient population is described in [Table 4]. Although patients who did not experience delirium were more likely to have had recent surgery and inhaled anesthetic exposure, no significant difference was seen between the nondelirium and delirium groups when considering blood loss from all surgical procedures, total surgical time, and total duration of inhaled anesthetic exposure.
Table 4: Surgical risk factors

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Potentially deliriogenic medications administered to this patient population during the course of their hospitalization are provided in [Table 5] and [Table 6]. Those patients that received diazepam and midazolam were more likely to develop delirium; this relationship held with predelirium versus total dose, given in lorazepam equivalents, of both diazepam and midazolam. Propofol dose as well as dexmedetomidine use and dose were also associated with the development of delirium. Total opioid dose, reported in fentanyl equivalents, was associated with the development of delirium; this was predominantly driven by fentanyl and hydromorphone administration. Cefepime, vancomycin, azithromycin, and piperacillin use were also associated with the development of delirium; however, no significance was seen when considering the dose of these medications. Neither use nor total dose of corticosteroids or medications with significant anticholinergic properties was associated with the development of delirium in our study population.
Table 5: Benzodiazepines, sedatives, opioids

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Table 6: Antibiotics, steroids, and drugs with anticholinergic properties

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The multivariate analysis for the evaluation of independent association of opioids, benzodiazepines, severity of disease, age, and presence of COVID-19 with the development of delirium is presented in [Table 7]. Only opioids, benzodiazepines, and estimated mortality by APACHE IV were independently associated with the development of delirium. Neither COVID-19 nor age was associated with the development of delirium after adjustment for important covariates.
Table 7: Multivariate analysis, receiving operator curves model 0.97

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   Discussion Top

In this prospective cohort of critically ill patients admitted to the ICU, we identified that delirium was prevalent in COVID-19 patients, with 20 (51.3%) of those in our study developing this syndrome. However, after adjustment for important confounders, our data showed that SARS-CoV-2 infection was not an independent risk factor for the development of delirium. The association of critical illness, indicated here through APS and APACHE IV, with the development of delirium was established.[7],[9],[11],[13] Many of the aforementioned variables that demonstrated a significant association with delirium are common to critically ill patients treated in the ICU. Such factors include the following: use of CRRT, ECMO, and mechanical ventilation; immunosuppression; vital signs such as tachycardia and tachypnea; and laboratory abnormalities including leukocytosis and acidemia. Sepsis and septic shock, like severe COVID-19, result in significant systemic inflammation; it is the release of proinflammatory cytokines associated with critical illness that is thought to be the proximate cause of delirium.[30],[31],[32],[33] Based on our findings, COVID-19 seems to be associated with the development of delirium in the critically ill due to other factors associated with illness severity in this condition and not because of some unique property intrinsic to SARS-CoV-2. It remains possible that in other phenotypes of COVID-19, such as less severe illness or CNS predominant disease, direct CNS inflammation may lead to delirium, as well as chronic encephalopathy or neuropsychiatric sequela.

The exact mechanism by which COVID-19 contributes to the development of delirium remains to be elucidated.[2] The effects of SARS-CoV-2 on the brain are likely multifactorial, with insult occurring both directly and indirectly.[1],[2],[3],[4],[9],[10],[18],[22],[34],[35],[36],[37] Direct CNS invasion is theoretically possible through either retrograde axonal transport or hematogenous spread.[2],[10],[13],[34],[35] Considering the common finding of anosmia,[2],[19],[23] at the outset of the pandemic, there were concerns that SARS-CoV-2 could result in encephalitis by infecting olfactory neurons.[2],[9] However, subsequent studies have shown that these symptoms likely result from an infection of supporting cells in the epithelium.[23]

Alternatively, direct neuroinvasion may occur due to the presence of angiotensin-converting enzyme 2, the receptor to which the virus spike protein binds on neurons, astrocytes, and oligodendrocytes..[2],[3],[7],[9],[11],[13],[14] Those cells found in the circumventricular organs are thought to be particularly susceptible to infection due to vascularization and permeability of the local blood–brain barrier.[2],[9],[12],[19] However, despite case reports of encephalitis,[19],[35] the paucity of patients in which SARS-CoV-2 is detected in the cerebrospinal fluid by PCR suggests other factors play a more significant role in the development of delirium than direct neuroinvasion.[1],[2],[19],[23] Furthermore, COVID-19 is associated with systemic coagulopathy and vasculopathy, resulting in macro-and microvascular pathology, both of which may contribute to the neurocognitive findings seen in these patients.[1],[2],[3],[23]

Severe COVID-19 results in significant systemic inflammation.[1],[4],[9],[21] The release of cytokines and chemokines increases blood–brain barrier permeability and activates resident neuroglial cells; both events are associated with the development of delirium.[1],[2],[9],[19],[23],[24] Although the pathogenesis of severe COVID-19 has been described as being contributed to by the occurrence of a cytokine storm,[7],[9],[16],[23] this phenomenon is not unique to SARS-CoV-2 infection; similar cytokine levels are seen in ARDS and sepsis secondary to bacterial infection.[1],[18] It is hypothesized that the preeminent cause of delirium in COVID-19 patients results from this mechanism.[6],[7],[10],[19],[21],[23]

Opioids, benzodiazepines, and certain sedatives are known to be deliriogenic;[6],[7],[15],[31],[38],[39],[40],[41] these medications are commonly used in the ICU. Our study shows a relationship between both diazepam and midazolam usage and dose with the development of delirium. Propofol showed a dose, but not use, related association with delirium. We suspect that this results from the dual utilization of this medication to induce anesthesia and for prolonged ICU sedation; during which significantly greater doses are administered. Both fentanyl and hydromorphone dose were correlated with the development of delirium, as was total opioid administration. Both opioids and benzodiazepines withstood multivariate analysis regarding their contributions to the development of delirium. Interestingly, anticholinergic medications, which have been associated with delirium,[15],[42] did not increase the risk of delirium in this population. A possible explanation may be related to cognitive reserve (i.e., baseline cognitive resilience). In this cohort, younger and more severely ill patients developed delirium; anticholinergic medications more commonly increase the risk of delirium in older patients who are more likely to have underlying cognitive impairment or a lower cognitive reserve.[42] In addition, age has been identified as an independent risk factor for the development of delirium.[15] Initial analysis showed that, in our patient population, the age of patients that did not develop delirium was greater compared to those who did. However, after adjusting for LOS (longer LOS resulted in a higher risk of developing delirium; surgical patients had a shorter LOS and were significantly younger), the age difference was no longer noted between the two groups.

Our study had several limitations including its modest size, performance at a single center, and imbalance between the size of the delirium and nondelirium groups. An additional limitation arose from the inclusion of surgical patients in our study population. Surgery is a well-established risk factor for the development of delirium; this is also an inflammatory cytokine-driven process.[43],[44] However, those patients in our study who recently had surgery were less likely to experience delirium. This unexpected finding is explained by the elective nature of many of the surgical procedures performed on older patients that required only shorter duration ICU and hospital courses. This had the effect of limiting many of the predisposing factors that otherwise contribute to the development of this syndrome, in our surgical patients. We acknowledge this limitation of our study and suggest thatfuture studies confirm our results in a patient population consisting of exclusively nonsurgical patients. In addition, a multicenter prospective study involving a large patient population is necessary to confirm and further characterize the association between COVID-19 and delirium.

   Conclusion Top

Although delirium is prevalent in COVID-19 patients, our data suggest that SARS-CoV-2 infection in critically ill patients is not an independent risk factor for its development. It is critical illness itself, denoted by APACHE IV, that accounts for the high rates of delirium in COVID-19 patients. Investigation of COVID-19-related cytokine release, which is associated with the development of delirium in septic shock and other infectious etiologies of critical illness,[30],[31],[32],[33] may further elucidate the mechanism by which SARS-CoV-2 causes delirium in these patients.

Research quality and ethics statement

This study was approved by the IRB at the Mayo Clinic (Approval # 18-005104; Approval date January 26, 2019). The authors followed the applicable EQUATOR Network (http://www.equator-network.org) guidelines, specifically the STROBE Guidelines, during the conduct of this research project.



Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Hawkins M, Sockalingam S, Bonato S, Rajaratnam T, Ravindran M, Gosse P, et al. A rapid review of the pathoetiology, presentation, and management of delirium in adults with COVID-19. J Psychosom Res 2021;141:110350.  Back to cited text no. 1
Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol 2021;268:3059-71.  Back to cited text no. 2
Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19: A literature review. J Clin Neurosci 2020;77:8-12.  Back to cited text no. 3
Justyna W. COVID-19: What do we need to know about ICU delirium during the SARS-CoV-2 pandemic? Physiol Behav 2017;176:139-48.  Back to cited text no. 4
Verhoef PA, Kannan S, Sturgill JL, Tucker EW, Morris PE, Miller AC, et al. Severe acute respiratory syndrome-associated coronavirus 2 infection and organ dysfunction in the ICU: Opportunities for translational research. Crit Care Explor 2021;3:e0374.  Back to cited text no. 5
Baller EB, Hogan CS, Fusunyan MA, Ivkovic A, Luccarelli JW, Madva E, et al. Neurocovid: Pharmacological Recommendations for Delirium Associated With COVID-19. Psychosomatics 2020;61:585-96.  Back to cited text no. 6
de Sousa Moreira JL, Barbosa SMB, Vieira JG, Chaves NCB, Felix EBG, Feitosa PWG, et al. The psychiatric and neuropsychiatric repercussions associated with severe infections of COVID-19 and other coronaviruses. Prog Neuro-Psychopharmacology Biol Psychiatry 2021;106:110159.  Back to cited text no. 7
Cipriani G, Danti S, Nuti A, Carlesi C, Lucetti C, Di Fiorino MA complication of coronavirus disease 2019: delirium. Acta Neurol Belg 2020;120:927-32.  Back to cited text no. 8
Verkhratsky A, Li Q, Melino S, Melino G, Shi Y. Can COVID-19 pandemic boost the epidemic of neurodegenerative diseases? Biol Direct 2020;15:1-8.  Back to cited text no. 9
Orsucci D, Ienco EC, Nocita G, Napolitano A, Vista M. Neurological features of COVID-19 and their treatment: A review. Drugs Context 2020;9:1-12.  Back to cited text no. 10
Divani AA, Andalib S, Biller J, Napoli DM, Moghimi N, Rubinos CA, et al. Central Nervous System Manifestations Associated with COVID-19. Curr Neurol Neurosci Rep 2020;20.  Back to cited text no. 11
Garcez FB, Aliberti MJR, Poco PCE, Hiratsuka M, Takahashi S de F, Coelho VA, et al. Delirium and Adverse Outcomes in Hospitalized Patients with COVID-19. J Am Geriatr Soc 2020;68:2440-6.  Back to cited text no. 12
Emmerton D, Abdelhafiz A. Delirium in Older People with COVID-19: Clinical Scenario and Literature Review. SN Compr Clin Med 2020;2:1790-7.  Back to cited text no. 13
Garg RK, Paliwal VK, Gupta A. Encephalopathy in patients with COVID-19: A review. J Med Virol 2021;93:206-22.  Back to cited text no. 14
Wilson JE, Mart MF, Cunningham C, Shehabi Y, Girard TD, MacLullich AMJ, et al. Delirium. Nat Rev Dis Prim 2020;6.  Back to cited text no. 15
Bellocchio L, Bordea IR, Ballini A, Lorusso F, Hazballa D, Isacco CG, et al. Environmental issues and neurological manifestations associated with covid-19 pandemic: New aspects of the disease? Int J Environ Res Public Health 2020;17:1-11.  Back to cited text no. 16
Zazzara MB, Penfold RS, Roberts AL, Lee KA, Dooley H, Sudre CH, et al. Probable delirium is a presenting symptom of COVID-19 in frail, older adults: a cohort study of 322 hospitalised and 535 community-based older adults. Age Ageing 2021;50:40-8.  Back to cited text no. 17
Andrews LJ, Benken ST. COVID-19: ICU delirium management during SARS-CoV-2 pandemic-pharmacological considerations. Crit Care 2020;24:375.  Back to cited text no. 18
Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID-19. J Alzheimers Dis. 2020;76:3-19.  Back to cited text no. 19
Hariyanto TI, Putri C, Hananto JE, Arisa J, Fransisca V Situmeang R, et al. Delirium is a good predictor for poor outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review, meta-analysis, and meta-regression. J Psychiatr Res 2021;142:361-8.  Back to cited text no. 20
Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic. The Lancet Psychiatry 2020;7:611-27.  Back to cited text no. 21
O'Hanlon S, Inouye SK. Delirium: a missing piece in the COVID-19 pandemic puzzle. Age Ageing 2020;49:497-8.  Back to cited text no. 22
Solomon T. Neurological infection with SARS-CoV-2-the story so far. Nat Rev Neurol 2021;17:65-6.  Back to cited text no. 23
Valiuddin HM, Kalajdzic A, Rosati J, Boehm K, Hill D. Update on neurological manifestations of SARS-CoV-2. West J Emerg Med 2020;21:45-51.  Back to cited text no. 24
Ely EW, Bernard GR, Speroff T, Gautam S, Dittus R, May L, et al. Delirium in mechanically ventilated patients: Validity and reliability of the Confusion Assessment Method for the intensive care unit (CAM-ICU). J Am Med Assoc 2001;286:2703-10.  Back to cited text no. 25
American Psychiatric Association. Neurocognitive Disorders. Diagnostic Stat Man Ment Disord 2013; 5th ed, APA Press, Washington, DC 2013.  Back to cited text no. 26
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-10.  Back to cited text no. 27
Apache IV Score n.d. https://intensivecarenetwork.com/Calculators/Files/Apache4.html. [Last accessed on 2021 Apr 22].  Back to cited text no. 28
Vincent J-L, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med 1996;22:707-10.  Back to cited text no. 29
Oldham MA, Flaherty JH, Maldonado JR. Refining Delirium: A Transtheoretical Model of Delirium Disorder with Preliminary Neurophysiologic Subtypes. Am J Geriatr Psychiatry 2018;26:913-24.  Back to cited text no. 30
Marcantonio ER. Delirium in hospitalized older adults. N Engl J Med 2017;377:1456-66.  Back to cited text no. 31
Atterton B, Paulino MC, Povoa P, Martin-Loeches I. Sepsis associated delirium. Medicina (Kaunas) 2020;56:240.  Back to cited text no. 32
Maldonado JR. Delirium pathophysiology: An updated hypothesis of the etiology of acute brain failure. Int J Geriatr Psychiatry 2018;33:1428-57.  Back to cited text no. 33
Østergaard L. SARS CoV-2 related microvascular damage and symptoms during and after COVID-19: Consequences of capillary transit-time changes, tissue hypoxia and inflammation. Physiol Rep 2021;9:e14726.  Back to cited text no. 34
Bougakov D, Podell K, Goldberg E. Multiple neuroinvasive pathways in COVID-19. Mol Neurobiol 2021;58:564-75.  Back to cited text no. 35
Dinakaran D, Manjunatha N, Naveen Kumar C, Suresh BM. Neuropsychiatric aspects of COVID-19 pandemic: A selective review. Asian J Psychiatr 2020;53:102188.  Back to cited text no. 36
Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, et al. Neurological associations of COVID-19. Lancet Neurol 2020;19:767-83.  Back to cited text no. 37
Dabrowski W, Siwicka-Gieroba D, Gasinska-Blotniak M, Zaid S, Jezierska M, Pakulski C, et al. Pathomechanisms of non-traumatic acute brain injury in critically Ill patients. Medicina (Kaunas) 2020;56:469.  Back to cited text no. 38
Reade MC, Finfer S. Sedation and delirium in the Intensive Care Unit. N Engl J Med 2014;370:444-54.  Back to cited text no. 39
Mattison ML. Delirium. Ann Intern Med 2020;173:ITC49-64.  Back to cited text no. 40
Maldonado JR. Acute brain failure: Pathophysiology, diagnosis, management, and sequelae of delirium. Crit Care Clin 2017;33:461-519.  Back to cited text no. 41
Maldonado JR. Neuropathogenesis of delirium: Review of current etiologic theories and common pathways. Am J Geriatr Psychiatry 2013;21:1190-222.  Back to cited text no. 42
Vasunilashorn SM, Ngo L, Inouye SK, Libermann TA, Jones RN, Alsop DC, et al. Cytokines and postoperative delirium in older patients undergoing major elective surgery. J Gerontol A Biol Sci Med Sci 2015;70:1289-95.  Back to cited text no. 43
Yang T, Velagapudi R, Terrando N. Neuroinflammation after surgery: From mechanisms to therapeutic targets. Nat Immunol 2020;21:1319-26.  Back to cited text no. 44


  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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